title: TGF-β-activated kinase 1 mediates mechanical stress-induced IL-6 expression in osteoblasts.
abstract: Mechanical stress plays a key role in bone remodeling. Previous studies showed that loading of mechanical stretch induces a rapid Ca(2+) influx and subsequent activation of stress-activated protein kinase pathways in osteoblasts. However, the activation mechanism and its significance in bone remodeling have not been fully elucidated. Here we show that TAK1 MAPKKK was activated by cyclic stretch loading of MC3T3-E1 cells. Knockdown of TAK1 attenuated the stretch-induced activation of JNK, p38, and NF-κB. Extracellular (EGTA) or intracellular (BAPTA/AM) Ca(2+) chelator prevented the stretch-induced activation of TAK1. Activation of TAK1 and its associated downstream signaling pathways were also suppressed by CaMKII inhibitors (KN-93 and KN-62). Furthermore, TAK1-mediated downstream pathways cooperatively induced the expression of IL-6 mRNA in the stretched MC3T3-E1 cells. We also confirmed that TAK1 mediates cyclic stretch-induced IL-6 protein synthesis in the cells using immunoblotting and ELISA. Finally, stretch loading of murine primary osteoblasts induced the expression of IL-6 mRNA via TAK1. Collectively, these data suggest that stretch-dependent Ca(2+) influx activates TAK1 via CaMKII, leading to the enhanced expression of IL-6 through JNK, p38, and NF-κB pathways in osteoblasts.
authors.affiliation: Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Fukuno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsui
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kanda
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Sasaki
authors.forename: Takayasu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Shinri
authors.initials: S
authors.lastname: Tamura
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors; D002460:Cell Line; D055785:Gene Knockdown Techniques; D015850:Interleukin-6 / Q000096:biosynthesis*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000201:enzymology / Q000502:physiology*; D013314:Stress, Mechanical; D013449:Sulfonamides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7; D000096926:Benzenesulfonamides
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D015850:Interleukin-6; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D013449:Sulfonamides; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C072105:KN 93; D000096926:Benzenesulfonamides; C063302:KN 62